US7964181B2ExpiredUtilityPatentIndex 51
Amino acid surrogates for peptidic constructs
Est. expiryMar 30, 2026(expired)· nominal 20-yr term from priority
C07K 14/58C07K 7/16C07D 403/04
51
PatentIndex Score
1
Cited by
47
References
35
Claims
Abstract
Ring-constrained amino acid surrogates of formula I: where R 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7 , and y are as defined in the specification, methods for synthesizing ring-constrained amino acid surrogates of formula I, methods of use of ring-constrained amino acid surrogates of formula I, including use in linear or cyclic compounds which include a plurality of amino acid residues and one or more ring-constrained amino acid surrogates of formula I and linear or cyclic compounds which include a plurality of amino acid residues and one or more ring-constrained amino acid surrogates of formula I.
Claims
exact text as granted — not AI-modified1. A compound having a formula of structure I:
or a synthetically acceptable salt thereof, wherein:
R 1 is a group of a formula:
R 2 is H or alkyl;
R 3 is H or a first nitrogen protecting group;
R 4 is H, alkyl, (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(H)R 11 , (CH 2 ) m C(═O)OR 11 , (CH 2 ) q OH, (CH 2 ) q OBn, (CH 2 ) q Oallyl, (CH 2 ) m C(═O)N(R 8 ) 2 , or (CH 2 ) m C(═O)N(R 8 )(CH 2 ) p N(R 8 ) 2 ;
R 5 is H or alkyl;
R 6a is H, alkyl, (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(H)R 11 , (CH 2 ) m C(═O)OR 11 , (CH 2 ) q OH, (CH 2 ) q OBn, (CH 2 ) q Oallyl, (CH 2 ) m C(═O)N(R 8 ) 2 , or (CH 2 ) m C(═O)N(R 8 )(CH 2 ) p N(R 8 ) 2 ;
R 6b is H or alkyl;
provided that one of R 4 and R 6a is H or alkyl and the other of R 4 and R 6a is (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(H)R 11 , (CH 2 ) m C(═O)OR 11 , (CH 2 ) q OH, (CH 2 ) q OBn, (CH 2 ) q Oallyl, (CH 2 ) m C(═O)N(R 8 ) 2 , or (CH 2 ) m C(═O)N(R 8 )(CH 2 ) p N(R 8 ) 2 ;
R 7 is H, C(═O)alkyl, C(═O)(CH 2 ) m (NR 8 ) 2 , alkyl, aralkyl, or aryl;
each occurrence of R 8 is independently H, aryl, or alkyl;
R 11 is a peptide solid support;
R 12 is H or a second nitrogen protecting group;
each occurrence of m is an independent integer having a value between 0 and 6;
each occurrence of q is an independent integer having a value between 1 and 6;
p is an integer having a value between 1 and 10; and
y is 0 or 1.
2. The compound of claim 1 , wherein y is 1.
3. The compound of claim 1 , wherein y is 0.
4. The compound of claim 1 , wherein R 4 is (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(R 8 ) 2 , (CH 2 ) m C(═O)N(H)R 11 , or (CH 2 ) m C(═O)OR 11 , and R 6a is H or alkyl.
5. The compound of claim 1 , wherein R 6a is (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(R 8 ) 2 , (CH 2 ) m C(═O)N(H)R 11 , or (CH 2 ) m C(═O)OR 11 , and R 4 is H or alkyl.
6. The compound of claim 1 , wherein R 3 is a group of a formula:
and R 9 is tert-butyl, allyl, or a group of a formula:
7. The compound of claim 1 , wherein R 1 is the group of the formula:
and R 12 is H or triphenylmethylene, tert-butyloxycarbonyl, toluenesulphonyl, formyl, nitro or benzyloxycarbonyl and m is, for R 1 , an integer having a value between 2 and 6.
8. The compound of claim 1 , wherein R 7 is H.
9. The compound of claim 1 having a formula:
or a synthetically acceptable salt thereof, wherein:
R 6a is H or alkyl; and
R 9 is tert-butyl, allyl, or a group of a formula:
10. The compound of claim 9 , wherein R 1 is the group of the formula:
and R 12 is H or triphenylmethylene, tert-butyloxycarbonyl, toluenesulphonyl, formyl, nitro or benzyloxycarbonyl and m is, for R 1 , an integer having a value between 2 and 6.
11. The compound of claim 9 , wherein R 7 is H.
12. The compound of claim 9 , wherein R 4 is (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(R 8 ) 2 , or (CH 2 ) m C(═O)N(H)R 11 .
13. The compound of claim 1 having a formula:
or a synthetically acceptable salt thereof, wherein:
R 1 is the group of the formula:
R 4 is (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(H)R 11 , (CH 2 ) q OH, (CH 2 ) q OBn, (CH 2 ) q Oallyl, (CH 2 ) m C(═O)N(R 8 ) 2 , or (CH 2 ) m C(═O)N(R 8 )(CH 2 ) p N(R 8 ) 2 ;
R 6 is H or alkyl; and
m is, for R 1 , an integer having a value between 2 and 6.
14. The compound of claim 13 , wherein R 1 is the group of the formula:
and R 12 is H or triphenylmethylene, tert-butyloxycarbonyl, toluenesulphonyl, formyl, nitro or benzyloxycarbonyl and m is, for R 1 , an integer having a value between 2 and 6.
15. The compound of claim 13 , wherein R 7 is H.
16. The compound of claim 13 , wherein R 4 is (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(R 8 ) 2 , (CH 2 ) m C(═O)N(H)R 11 , or (CH 2 ) m C(═O)OR 11 .
17. The compound of claim 1 having a formula:
or a synthetically acceptable salt thereof, wherein:
R 1 is a group of a formula:
R 4 is H or alkyl;
R 6a is (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(H)R 11 , (CH 2 ) q OH, (CH 2 ) q OBn, (CH 2 ) q Oallyl, (CH 2 ) m C(═O)N(R 8 ) 2 , or (CH 2 ) m C(═O)N(R 8 )(CH 2 ) p N(R 8 ) 2 ; and
m is, for R 1 , an integer having a value between 2 and 6.
18. The compound of claim 17 , wherein R 3 is a group of a formula:
and R 9 is tert-butyl, allyl, or a group of a formula:
19. The compound of claim 17 , wherein R 1 is alkyl-N(R 8 ) 2 , alkyl-OR 8 , (CH 2 ) m —C(═O)OR 8 , C(═O)OR 8 , alkyl-S—R 8 , alkyl-C(═O)N(R 8 ) 2 , or the group of the formula:
and R 12 is H or triphenylmethylene, tert-butyloxycarbonyl, toluenesulphonyl, formyl, nitro or benzyloxycarbonyl and m is, for R 1 , an integer having a value between 2 and 6.
20. The compound of claim 17 , wherein R 6a is (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(R 8 ) 2 , (CH 2 ) m C(═O)N(H)R 1 , or (CH 2 ) m C(═O)OR 11 .
21. The compound of claim 17 , wherein R 7 is H.
22. The compound of claim 1 having a formula:
or an enantiomer, stereoisomer or diastereoisomer thereof, or a synthetically acceptable salt thereof, wherein:
R 4 is H or alkyl; and
R 9 is tert-butyl, allyl, or a group of a formula:
23. The compound of claim 22 , wherein R 1 is the group of the formula:
and R 12 is H or triphenylmethylene, tert-butyloxycarbonyl, toluenesulphonyl, formyl, nitro or benzyloxycarbonyl and m is, for R 1 , an integer having a value between 2 and 6.
24. The compound of claim 22 , wherein R 7 is H.
25. The compound of claim 22 , wherein R 4 is (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(R 8 ) 2 , (CH 2 ) m C(═O)N*H)R 11 , or (CH 2 ) m C(═O)OR 11 .
26. The compound of claim 22 , wherein R 3 is a group of a formula:
and R 9 is tert-butyl, allyl, or a group of a formula:
27. The compound of claim 22 , wherein R 6a is (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(H)R 11 , (CH 2 ) m C(═O)OR 11 , (CH 2 ) q OH, (CH 2 ) q OBn, (CH 2 ) q Oallyl, (CH 2 ) m C(═O)N(R 8 ) 2 , or (CH 2 ) m C(═O)N(R 8 )(CH 2 ) p N(R 8 ) 2 .
28. The compound of claim 22 , wherein R 7 is H.
29. A method of synthesizing a peptide comprising a group of the formula:
said method comprising the step of reacting a compound having a formula of structure I:
or a synthetically acceptable salt thereof, with an N-protected amino acid,
wherein:
R 1 is a group of a formula:
R 2 is H or alkyl;
R 3 is H or a first nitrogen protecting group;
R 4 is H, alkyl, (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(H)R 11 , (CH 2 ) m C(═O)OR 11 , (CH 2 ) q OH, (CH 2 ) q OBn, (CH 2 ) q Oallyl, (CH 2 ) m C(═O)N(R 8 ) 2 , or (CH 2 ) m C(═O)N(R 8 )(CH 2 ) p N(R 8 ) 2 ;
R 5 is H or alkyl;
R 6a is H, alkyl, (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(H)R 11 , (CH 2 ) m C(═O)OR 11 , (CH 2 ) q OH, (CH 2 ) q OBn, (CH 2 ) q Oallyl, (CH 2 ) m C(═O)N(R 8 ) 2 , or (CH 2 ) m C(═O)N(R 8 )(CH 2 ) p N(R 8 ) 2 ;
R 6b is H or alkyl;
provided that one of R 4 and R 6a is H or alkyl and the other of R 4 and R 6a is (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(H)R 11 , (CH 2 ) m C(═O)OR 11 , (CH 2 ) q OH, (CH 2 ) q OBn, (CH 2 ) q Oallyl, (CH 2 ) m C(═O)N(R 8 ) 2 , or (CH 2 ) m C(═O)N(R 8 )(CH 2 ) p N(R 8 ) 2 ;
R 7 is H, C(═O)alkyl or C(═O)(CH 2 ) m (NR 8 ) 2 ;
each occurrence of R 8 is independently H, aryl, or alkyl;
R 11 is a peptide solid support;
R 12 is H or a second nitrogen protecting group;
each occurrence of m is an independent integer having a value between 0 and 6;
each occurrence of q is an independent integer having a value between 1 and 6;
p is an integer having a value between 1 and 10; and
y is 0 or 1.
30. A compound having a formula:
or a synthetically acceptable salt thereof, wherein:
R 3 is H or a first nitrogen protecting group;
each occurrence of R 8 is independently H, aryl, or alkyl; and
R 13 is OH or N(R 8 ) 2 .
31. The compound of claim 30 , wherein R 3 is a first nitrogen protecting group of a formula:
and R 9 is tert-butyl, allyl, or a group of a formula:
32. A compound having a formula of structure I:
or a synthetically acceptable salt thereof, wherein:
R 1 is alkyl-OR 8 , alkyl-C(═O)OR 8 , C(═O)OR 8 , alkyl-S—R 8 , alkyl-C(═O)N(R 8 ) 2 , or a group of a formula:
R 2 is H or alkyl;
R 3 is a first nitrogen protecting group of a formula:
R 4 is H, alkyl, (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(H)R 11 , (CH 2 ) m C(═O)OR 11 , (CH 2 ) q OH, (CH 2 ) q OBn, (CH 2 ) q Oallyl, (CH 2 ) m C(═O)N(R 8 ) 2 , or (CH 2 ) m C(═O)N(R 8 )(CH 2 ) p N(R 8 ) 2 ;
R 5 is H or alkyl;
R 6a is H, alkyl, (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(H)R 11 , (CH 2 ) m C(═O)OR 11 , (CH 2 ) q OH, (CH 2 ) q OBn, (CH 2 ) q Oallyl, (CH 2 ) m C(═O)N(R 8 ) 2 , or (CH 2 ) m C(═O)N(R 8 )(CH 2 ) p N(R 8 ) 2 ;
R 6b is H or alkyl;
provided that one of R 4 and R 6a is H or alkyl and the other of R 4 and R 6a is (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(H)R 11 , (CH 2 ) m C(═O)OR 11 , (CH 2 ) q OH, (CH 2 ) q OBn, (CH 2 ) q Oallyl, (CH 2 ) m C(═O)N(R 8 ) 2 , or (CH 2 ) m C(═O)N(R 8 )(CH 2 ) p N(R 8 ) 2 ;
R 7 is H, C(═O)alkyl, C(═O)(CH 2 ) m (NR 8 ) 2 , alkyl, aralkyl, or aryl;
each occurrence of R 8 is independently H, aryl, or alkyl;
R 9 is tert-butyl, allyl, or a group of a formula:
R 11 is a peptide solid support;
R 12 is H or a second nitrogen protecting group;
each occurrence of m is an independent integer having a value between 0 and 6;
each occurrence of q is an independent integer having a value between 1 and 6;
p is an integer having a value between 1 and 10; and
y is 0 or 1.
33. The compound of claim 32 , wherein y is 1.
34. The compound of claim 32 , wherein y is 0.
35. The compound of claim 34 , wherein R 4 is (CH 2 ) m C(═O)OH, (CH 2 ) m C(═O)N(R 8 ) 2 , (CH 2 ) m C(═O)N(H)R 11 , or (CH 2 ) m C(═O)OR 11 , and R 6a is H or alkyl.Cited by (0)
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